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Mechanism of apoptosis, initiated by damage to cellular molecules or cellular signals during tissue remodeling or wound healing, resulting in cytochrome C release from mitochondria. This release is regulated by Bax/Bc12 on the outer mitochondrial membranes, and results in activation of caspases and an apoptotic-specific nuclease. These degradative enzymes normally are associated with specific caspase-sensitive inhibitors, so that once apoptosis is set in train an autocatalytic process results with positive feedback to produce irreversible cellular degradation.
and others 1995; Kumar 1995; Leonard and others 1995; Caelles and others 1994; Canman and others 1994; Jacobson and Evan 1994; Meyn and others 1994; Lowe and others 1993; Waddick and others 1993; Uckun and others 1992). Fluctuating oxygen levels leading to oxidative bursts and the production of reactive oxygen intermediates can trigger apoptosis through their activation of p53. The mitochondria play an important role in the initial events leading to apoptosis, and one of the first signals is the release of cytochrome C into the cytoplasm (Reed 1997), which, with dATP activates a caspase cascade involving especially caspase-3 (Li and others 1997). The gene product Bc1-2 is on the outer mitochondrial membrane, where it regulates ion flow and, under conditions of normal expression, suppresses apoptosis. Its expression is induced by p53 (Pourzand and others 1997; Chen and others 1995). Two other proteins, Bax and Ced-4, bind to Bcl-2 and are inactive in bound form, but on release they further stimulate the release of apoptosis-initiating factors, which eventually activate the caspase class of proteases (Kumar 1995). One pathway to apoptosis is thus determined by the ratio of Bax/Bcl-2 expression. Many other proteins are involved in apoptosis, including many members of the caspase family of proteases and caspase inhibitors which regulate the process in different tissues and under various stresses. Other pathways by which apoptosis is activated involve the cytokines, such as TNF1-alpha, and the signal transducer and activator protein STAT1 (Kumar and